Content Reviewers:Antonella Melani, MD
A 5 day old newborn infant girl named Emily is brought to the emergency department due to vomiting, diarrhea, and poor feeding.
Her mother also mentions that Emily seems to be tired and sleepy all day long.
Physical examination reveals bilateral clouding of the lens, along with yellowing of the sclera.
Upon palpation of the abdomen, Emily’s liver appears enlarged.
Emily’s mother mentions that she lives in a remote area and gave birth at home.
You decide to run a urine dipstick test, which comes back negative for sugars, followed by a nonspecific urine test, which shows increased levels of reducing sugars.
Some days later, you see a 21 year old man of Asian descent named Chris, who’s complaining of repeated episodes of bloating, abdominal cramps, and excessive flatulence that are often associated with watery, frothy stool.
He has noticed that his symptoms tend to occur when he eats cheese or ice cream.
Upon further questioning, he denies any concomitant diseases or recent gastrointestinal infections.
Physical examination is unremarkable.
Okay, based on the history and initial presentation, both Emily and Chris seem to have some form of disorder of carbohydrate metabolism.
Carbohydrates are our main source of energy, and can be classified as simple or complex.
Simple carbohydrates include monosaccharides, which contain one sugar molecule, like glucose, fructose, and galactose; and disaccharides, where two sugar molecules are linked together.
Disaccharides include lactose, which is made up of glucose and galactose, and sucrose, which is formed when glucose links up with fructose.
On the other hand, complex carbohydrates include oligosaccharides and polysaccharides, which are respectively short and long chains made up of more than two sugar molecules.
All right, now, for your exams, the most high yield disorders of carbohydrate metabolism include pyruvate dehydrogenase complex deficiency, galactosemia, disorders of fructose metabolism, and lactose intolerance.
Let’s begin with pyruvate dehydrogenase complex deficiency or PDC deficiency.
This is mainly caused by mutations in the PDHA1 gene, which is located on the X chromosome.
So, PDC deficiency is an X-linked recessive disorder, which means that all carrier males develop the disease, because they only have one X chromosome and thus one PDHA1 gene available.
On the other hand, females have two X chromosomes, so having a single mutation makes them a carrier, and two mutations are needed to have the disease.
Now, the PDHA1 gene codes for one of the enzymes of the pyruvate dehydrogenase complex or PDC for short.
Normally, after a meal, glucose is broken down into pyruvate in the cytoplasm through a process called glycolysis.
Pyruvate can then enter the mitochondria, where a complex of three mitochondrial enzymes, called the pyruvate dehydrogenase complex, converts pyruvate into acetyl-CoA.
For your exams, remember that the pyruvate dehydrogenase complex requires a set of 5 cofactors to work properly.
To help you remember these 5 cofactors, think of the mnemonic “The Lovely Coenzymes For Nerds”, which stands for thiamine pyrophosphate, which is a derivative of thiamine or vitamin B1; lipoic acid; CoA; which is a derivative of pantothenic acid or vitamin B5; FAD, which is a riboflavin or vitamin B2 derivative; and NAD+, which is a niacin or vitamin B3 derivative.
Okay, so, with PDC deficiency, acetyl-CoA levels fall, causing the Krebs cycle to slow down, and as a result, there’s decreased production of ATP.
For your exams, keep in mind that this primarily affects cells with high energy requirements like neurons.
At the same time, pyruvate builds up, so it gets converted to lactate by the enzyme lactate dehydrogenase or LDH for short, as well as to alanine by alanine aminotransferase or ALT.
Symptoms of PDC deficiency typically begin during infancy and include lethargy or extreme lack of energy, hypotonia or weak muscle tone, and poor feeding.
In addition, PDC deficiency may lead to developmental delay, intellectual disability, and seizures.
For diagnosis, lab tests show elevated blood levels of alanine and, most importantly, lactate, which is known as lactic acidosis and it’s extremely high yield for your exams!
Treatment of PDC deficiency consists of correcting the acidosis, as well as adopting a ketogenic diet, which is a diet low in carbohydrates and high in fat and ketogenic amino acids like lysine or leucine.
This diet results in the generation of ketone bodies, which can be used as an alternative energy source by tissues around the body and especially, by the brain.
Okay, next is galactosemia, which refers to defects in the metabolism of galactose.
The normal pathway of galactose metabolism starts with the enzyme galactokinase, which converts galactose to galactose 1-phosphate, that can’t exit the cells.
Galactose 1-phosphate is then converted by the enzyme uridyltransferase to glucose 1-phosphate, which can then enter the gluconeogenesis pathway to make more glucose or the glycolysis pathway to produce energy.
Now, some of the galactose undergoes an alternate pathway, where it’s broken down by the enzyme aldose reductase into galactitol, which is then excreted in the urine.
For your exam, remember that there are two types of galactosemia.
The most common one is type I or classic galactosemia, which is caused by a deficiency in galactose-1-phosphate uridyltransferase or GALT for short; while type II galactosemia is caused by a deficiency of galactokinase.
Keep in mind is that both types are autosomal recessive, meaning that an individual needs to inherit two copies of the mutated gene, one from each parent, to develop the condition.
Now, both type I and type II galactosemia typically present early on, as soon as the infant begins breastfeeding, since breast milk contains lactose that’s digested by the enzyme lactase into galactose and glucose.
So, with galactosemia, all this galactose ends up being converted to galactitol by aldose reductase.
The excess galactitol mainly accumulates in the lens of the eye and attracts water, which ultimately causes the lens fiber to swell until they rupture.
Now, the main symptom of cataracts is a painless visual impairment that’s often bilateral, and these infants may present as a failure to track objects or to develop a social smile in response to someone else’s smile because they can’t see that well.
For your exams, another telltale sign is leukocoria or “white pupil”, which is an abnormal white reflection from the retina of the eye, also called a white pupillary reflex.
What you definitely need to know for your exams is that type I galactosemia is much more severe.
That’s because galactose can still be converted into galactose 1-phosphate.
So, symptoms include hepatomegaly or liver enlargement associated with jaundice.
In addition, there’s lethargy and intellectual disability, as well as nausea, vomiting, diarrhea, and poor feeding; which combined result in failure to thrive.
Diagnosis of galactosemia is based on blood tests that show elevated galactose in blood.
Some of the excess galactose is excreted in the urine, resulting in galactosuria.
Don’t let examiners confuse you by mentioning that a urine dipstick was negative for sugars!
Remember that this refers to glucose only, but there are nonspecific urine tests that can detect reducing sugars, such as galactose, fructose, and lactose.
So, if there's some reducing sugar other than glucose in the urine, we're gonna get a negative urine dipstick test and a positive reducing test.
In many countries, these tests are performed as a uniform newborn screening.
Diagnosis can be confirmed with a blood test by measuring reduced enzymatic activity of GALT or galactokinase, respectively for type I and II, and they’re both treated with a diet free of galactose and lactose for life.